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Abstract: This paper reviews current concepts regarding the pathophysiology, diagnostic evaluation, and treatment of microalbuminuria
and proteinuria in adults. Microalbuminuria (in diabetics) and proteinuria are early markers for potentially serious renal disease, and are
associated with increased risk of atherosclerotic cardiovascular disease.
Proteinuria also contributes to renal scarring, and accelerates the progression of chronic kidney disease to end-stage renal failure. Screening
of diabetics for microalbuminuria, and the initial workup of proteinuria,
should occur in the primary care setting. Reduction of microalbuminuria in diabetics may retard its progression to overt diabetic nephropathy. Therapy of renal diseases should aim for optimal blood pressure
control and the maximum possible reduction in urinary protein excretion. Angiotensin-converting en2yme inhibitor (ACE-I) and/or angiotensin-receptor blocker (ARB) therapy is the most effective measure to
achieve this. These drugs also provide protection against the cardiovascular problems that are highly prevalent in this patient population.
Key Words: angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, chronic kidney disease, microalbuminuria,
proteinuria
Definitions
Normal adults excrete less than 150 to 200 mg/d of protein in the urine.'^~"' Very little of this protein is albumin (less
than 1020 mg/d). Albumin excretion in the range of 30 to
300 mg/d or, as is more commonly repotted, 30 to 300 mg/g
of urinary creatinine, is referred to as microalbuminuria. At
these levels, standard dipsticks do not detect albumin in the
urine, and specific measurement of albumin using highly albumin-sensitive techniques is required. Although gender-specific limits for normal urinary albumin excretion have been
suggested (17 mg/g of creatinine for men and 25 mg/g in
women),'' for clinical purposes, using the same cut-off value
for both sexes is sufficient.
Key Points
Persistent microalbuminuria (in diabetics) and overt
proteinuria are important markers for the subsequent
development of progressive chronic kidney disease,
and are also associated with a high risk of cardiovascular disease.
The total daily urinary excretion of albumin or protein
is reliably quantitated by the ratio of their concentration to the concentration of creatinine in a random
urine sample. Testing a random sample of urine has
largely replaced the cumbersome 24-hour urine collection in clinical practice.
Reduction of microalbuminuria in diabetics and overt
proteinuria irrespective of etiology, together with strict
blood pressure control, is helpful in ameliorating the
progression of chronic kidney disease.
Identifying and correcting cardiovascular risk factors
are key aspects of managing microalbuminuric and
overtly proteinuric patients.
The use of an angiotensin-converting enzyme inhibitor (ACE-1) and/or an angiotensin-reeeptor blocker
(ARB) is the most effective way of ameliorating these
urinary abnormalities.
Screening for microalbuminuria and overt proteinuria,
and timely referral for nephrology evaluation of these
patients in the primary care setting, is critically
important.
0038-4348/04/9710-0969
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to exclude larger proteins such as globulins from the glomerular filtrate (size-barrier). The role of structural proteins, such
as nephrin, podocin, and a-actinin, normally present in the
slit-pores in preventing protein filtration has recently come to
be recognized.'^ Inherited abnormalities in these proteins result in hereditary forms of nephrotic syndrome.
Glomerular charge and size barriers allow the passage
into the glomerular filtrate of only small, positively charged
proteins such as ji-2 microglobulin and immunoglobulin light
chains, and small amounts of albumin. The proximal tubular
epithelium reabsorbs and catabolizes most of the proteins that
escape the glomerular barriers.^ Glomerular filtration of protein, therefore, contributes minimally to normal urine protein
content. Most of the protein in normal urine is the TammHorsfall glycoprotein secreted by the renal tubules.**"'" Table
1 shows the pathophysiologic mechanisms that underlie increased urinary protein excretion in various disorders.
Causes
Multiple myeloma; other paraproteinemic states.
Glomerular proteinuria
Selectiveloss of only the glomerular charge-barrier, albumin excreted
predominantly.^
Non-seleetiveloss of both the charge and size-barrier with excretion of
albumin and larger molecular weight proteins (such as IgG).^
Tubular proteinuria
Albumin and larger proteins restricted by intact glomerular barriers. Small
molecular weight proteins normally freely filtered at the glomerulus (such
as j3-2 microglobulin) escape reabsorption/catabolism because of renal
tubular damage.'''"
Posturai proteinuria
Abnormal protein excretion in the upright posture, with normal urinary
protein excretion in recumbency, probably due to exaggerated systemic and
glomerular hemodynamic responses in the upright posture.'''"'"'
"Admixture" proteinuria
Gross hematuria with tests for urinary protein detecting protein present in
blood mixed with urine. No renal pathology.
"Physiologic"/transient proteinuria
Probably due to transient glomerular hemodynamic changes.
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CME Topic
daily excretion of greater than 0.2 g but less than 3.5 g, and
values greater than 3.5 indicate a daily protein excretion of
more than 3.5 g.'"-'^
There may be significant day-to-day variations of up to
15 to 40% in daily total urinary protein excretion both in
normal subjects and those with renal disease. This is due to
the effects on urinary protein excretion of variables such as
physical activity, dietary salt and fluid intake, and blood pressure. There is also diurnal variation in urinary protein excretion (highest between 6 AM and noon). Hence the recommendation to check the second voided morning specimen to
measure the microalbumin or protein to creatinine ratio. However, for the purposes of clinical practice, the time of the day
at which the random urine sample is obtained is generally not
important.
It should be noted that in subjects with above- or belowaverage muscle mass, the random urine protein/tirine creatinine
ratio may not correspond numerically to the total 24-hour excretion of protein. For example, in a person with less than average muscle mass excreting only 600 mg/d of urinary creatinine, a random urine protein/urine creatinine ratio of 3.0
represents daily protein excretion of 1.8 g, whereas in a very
muscular individual excreting 1,500 mg/d of creatinine, the
same ratio of 3.0 will indicate daily protein excretion of 4.5 g.
The main value of the easily measured random urine protein/
urine creatinine ratio is to classify patients based on the magnitude of proteinuria, and consider in the differential diagnosis
renal disorders characterized by these different levels of urinary
protein excretion. The ratio is also an easy way of following the
trend in proteinuria over time in individual patients.
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trophy (both mediated by angiotensin II) in the initially undamaged nephrons, are implicated in the inexorably progressive renal damage.^'"'"^*' Hyperfiltration in intact remnant
glomeruli can compensate for the loss of function in the initially
damaged nephrons, but is eventually maladaptive. Elevated intraglomerular pressure and glomerular hypertrophy lead to progressive glomerulosclerosis, thus accelerating the loss of renal
function. Other factors contributing to the self-perpetuating loss
of renal function include systemic hypertension, high dietary
protein intake, anemia, hyperlipidemia, elevated calciumphosphate product resulting fi'om renal failure, intercurrent renal
insults (eg, the use of nephrotoxic drugs [nonsteroidal antiinflammatory drugs, iodinated radiologic contrast, aminoglycosides], pyelonephritis, obstructive uropathy), and cigarette
Over the past two decades proteinuria itself has been
implicated as a cause of progressive renal damage."'''' Several
large human trials have shown that the greater the magnitude
of baseline proteinuria, the faster the progression of renal
failure. Furthermore, the decrease in proteinuria during therapy in these trials correlated strongly with slower progression
of chronic kidney disease, independent of the degree of blood
pressure control.^^"^'* These observations suggest a pathogenic role for proteinuria in progressive renal injury. Therapy
is generally more effective in slowing the progression of
chronic renal failure in patients with heavy baseline proteinuria. However, a beneficial effect has also been shown in
patients with lesser levels of proteinuria.''^
In experimental studies, increased protein filtration across
the glomerular capillary wall and tubular reabsorption/
catabolism of larger than normal amount of filtered protein have
been shown to induce the production of pro-inflammatory and
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Causes
Normal individuals.
CME Topic
Stage
Glomerutar
filtration rate
(mL/min/1.73 m
>90
60-89
Comments
30-59
15-29
Diagnostic Evaluation of
Microalbuminuria and Overt Proteinuria
Microalbuminuria
Annual screening for microalbuminuria (if standard dipstick testing is negative) starting 5 years after the diagnosis of
type 1, and at the time of diagnosis of type 2 diabetes mellitus
(because it is difficult to time its onset) is recommended.^'*'^^
Albumin excretion can vary on a day-to-day basis depending
on factors such as vigorous physical activity. Thus, persistence of microalbuminuria needs to be confirmed by retesting
within 1 to 3 months before interventions to correct it are
undertaken.
Overt proteinuria
In healthy adults, periodic urinalysis to detect overt proteinuria is not recommended as a health-maintenance measure.^^ However, in the presence of risk factors for kidney
disease, such as diabetes mellitus and severe hypertension,
annual testing by dipstick for overt proteinuria is important.''" A positive dipstick test indicates the presence of
albumin in the urine, because it detects albumin almost exclusively, and obviates the need for ordering tests for microalbuminuria. In overtly proteinuric patients, monitoring
the excretion of total proteins in the urine rather than albumin
specifically is preferable.^' Measuring albumin specifically is
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Table 4. Laboratory studies in the evaluation of proteinuria: tests for assessing severity of the eausative renal
disease
Type of test
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Treatment of Proteinuria
There are three aspects to the treatment of the proteinuric
patient: corticosteroid and immunosuppressive therapy of the
causative renal disorder, correcting the clinical effects of proteinuria, and measures to reduce the quantity of urinary protein.
2004 Southern Medical Association
CME Topic
Table 5. Laboratory studies in the evaluation of proteinuria: tests for identifying etiology of causative renal disease"
Purpose of the test
Type of test
Blood glucose; glycosylated hemoglobin
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in affording renoprotection continues to be debated.'^^^' Proteinuria targets may not always be achieved despite maximal
therapy. In such patients, it should be ensured that at least the
blood pressure goals are achieved. The control of both systolic and diastolie blood pressure to recommended levels is
important. Besides blood pressure control and reduction of
proteinuria, other measures also help to ameliorate the progression of renal failure: dietary protein restriction, optimal
diabetes control, correction of calcium/phosphorous levels,
treatment of hyperlipidemia, correction of anemia, smoking
cessation, and avoidance of nephrotoxic agents (nonsteroidal
anti inflammatory agents, cyclooxygenase-2 inhibitors, aminoglycosides, radio-contrast)."'^-^'
Renin-angiotensin system blockade may not be unique in
conferring renoprotection. A large study showed that a
j3-blocker and an ACE-I were equally effective in diabetic
nephropathy.''' In the African-American Study of Kidney Disease, the amlodipine arm was terminated early because it was
inferior to ramipril in slowing the progression of renal failure,
but the double-blind comparison of ramipril to a /3-blocker is
continuing. 29
Conclusion
Microalbuminuria and overt proteinuria persisting on retesting the urine should be regarded as potentially serious
abnormalities. The quantity of protein excreted per day, the
serum creatinine level, and the calculated glomerular filtration rate determine the severity of the underlying renal disorder. Patients with overt proteinuria, >1 g/d (or random
urine protein/urine creatinine ratio > 1.0) or associated with
reduced renal function will benefit from evaluation by a nephrologist. Even with normal renal function and overt proteinuria of 0.2 to 1 g/d, nephrology consultation is indicated if
hypertension, systemic diseases which comtnonly involve the
kidneys (eg, diabetes mellitus, systemic lupus erythematosus), a history of use of medications or illicit drugs known to
cause proteinuria, or a family history of renal disease is
present. Type 1 diabetes of more than 5 years' duration, and
type 2 diabetes irrespective of known duration, are indications for annual testing for microalbuminuria. Importantly,
therapy in microalbuminuric or overtly proteinuric patients
should aim for blood pressure control to a level < 130 to 125
mm Hg systolic, and diastolic <80 to 75 mm Hg, and the
maximum possible reduction of microalbuminuria and overt
proteinuria to retard the development/progression of chronic
kidney disease. Mieroalbuminuric and overtly proteinuric
patients have a high risk of developing cardiovascular disease. In addition to focusing on renal disease, close attention
should be paid to correcting all risk factors for cardiovascular
disease in this patient population. The cornerstone of such
renal and cardiovascular protective therapy is the use of
ACE-ls and/or ARBs.
2004 Southern Medical Association
CME Topic
Table 7. Common problems encountered during the use of ACE-Is ARBs in patients with chronic kidney disease"
Problem
Hyperkalemia
Caused by decreased aldosterone levels resulting from blockade of the
renin-angiotensin system. This leads to decreased urinary and colonic
excretion of potassium.
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